The invention relates to novel 6-[(tetrazol-5-yl)-phenyl]phenanthridines, which are used in the pharmaceutical industry for the production of medicaments.
Chem. Ber. 1939, 72, 675-677, J. Chem. Soc., 1956, 4280-4283 and J. Chem. Soc. (C), 1971, 1805 describe the synthesis of partial hydrogenated 6-phenylphenanthridines. In the international patent applications WO97/35854 and WO97/28131 partial hydrogenated 6-phenylphenanthridines are described as cyclic nucleotide phosphodiesterase (PDE) inhibitors of type 4.
It has now been found that the novel 6-phenyl-phenanthridines, which are described below in greater detail, which differ from the prior art, in particular, by the substitution on the 6-phenyl ring, have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I 
in which
R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
R3 is hydrogen or 1-4C-alkyl,
R31 is hydrogen or 1-4C-alkyl,
or in which
R3 and R31 together are a 1-4C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together are an additional bond,
R6 is a phenyl radical substituted by R7, where
R7 is a tetrazol-5-yl radical substituted by a radical R8, where
R8 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where
Ar is a phenyl radical which is unsubstituted or substituted by R9 and/or R10, and
R9 and R10 independently of one another are halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl or 1 -4C-alkoxy,
and the salts of these compounds.
1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and, preferably, the ethyl and methyl radicals.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or b ranched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and, preferably, the ethoxy and methoxy radicals.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentyl methoxy are preferred.
Completely or predominantly fluorine-substituted 1-4C-alkoxy which may be mentioned are, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and, preferably, the difluoromethoxy radicals. xe2x80x9cPredominantlyxe2x80x9d in this connection means that more than half of the hydrogen atoms are substituted by fluorine atoms.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy (xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94) and the ethylenedioxy radicals (xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94).
If R3 and R31 together have the meaning 1-4C-alkylene, the positions 1 and 4 in compounds of the formula I are linked to one another by a 1-4C-alkylene bridge, 1-4C-alkylene representing straight-chain or branched alkylene radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the radicals methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94), trimethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94), 1,2-dimethylethylene [xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94] and isopropylidene [xe2x80x94C(CH3)2xe2x80x94].
If R5 and R51 together are an additional bond, then the carbon atoms in positions 2 and 3 in compounds of the formula I are linked to one another via a double bond.
1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
3-7C-Cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the cycloheptyl radicals. The 5-7C-cycloalkyl radicals cyclopentyl, cyclohexyl and cycloheptyl may be mentioned as preferred.
3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopentylmethyl and the cyclohexylmethyl radicals.
Ar-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the aryl radicals defined above. Examples which may be mentioned are the p-methoxybenzyl, the phenethyl and the benzyl radicals.
Halogen within the meaning of the invention is bromine, chlorine and fluorine.
Suitable salts for compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy. Those which are suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in salt preparationxe2x80x94depending on whether it is a mono- or polybasic acid and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
On the other handxe2x80x94for example if the tetrazol-5-yl radical R7 is substituted by R8=Hxe2x80x94 salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts which may be obtained initially as process products, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
According to expert""s knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula I.
Compounds of the formula I to be emphasized are those in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
or in which
R3 and R31 together are a 1-2C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together are an additional bond,
R6 is a phenyl radical substituted by R7, where
R7 is a tetrazol-5-yl radical substituted by a radical R8, where
R8 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where
Ar is a phenyl radical which is unsubstituted or substituted by R9 and/or R10, and
R9 and R10 independently of one another are 1-4C-alkyl or 1-4C-alkoxy,
and the salts of these compounds.
Compounds of the formula I particularly to be emphasized are those in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
or in which
R3 and R31 together are a 1-2C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together are an additional bond,
R6 is a phenyl radical substituted by R7, where
R7 is a tetrazol-5-yl radical substituted by a radical R8, where
R8 is hydrogen, 1-4C-alkyl, 5-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-2C-alkyl, where
Ar is a phenyl radical which is unsubstituted or substituted by R9, and
R9 is 1-2C-alkyl or 1-2C-alkoxy,
and the salts of these compounds.
Preferred compounds of the formula I are those in which
R1 is 1-4C-alkoxy,
R2 is 1-4C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R51 is hydrogen,
R6 is a phenyl radical substituted by R7, where
R7 is a tetrazol-5-yl radical substituted by R8, where
R8 is hydrogen, 1-4C-alkyl or 4-methoxybenzyl,
and the salts of these compounds.
Particularly preferred compounds of the formula I are those in which
R1 is methoxy or ethoxy,
R2 is methoxy or ethoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R51 is hydrogen,
R6 is a phenyl radical substituted by R7, where
R7 is a 2H-tetrazol-5-yl radical substituted by R8, where
R8 is hydrogen, ethyl or 4-methoxybenzyl,
and the salts of these compounds.
The compounds of the formula I are chiral compounds having chiral centers in the positions 4a and 10b and, depending on the meaning of the substituents R3, R31, R4, R5 and R51, further chiral centers in the positions 1, 2, 3 and 4. 
The invention therefore includes all conceivable pure diastereomers and pure enantiomers and their mixtures in any mixing ratio, including the racemates. The compounds of the formula I are preferred in which the hydrogen atoms in the positions 4a and 10b are cis to one another. Particularly preferred here are the pure cis-diastereomers and the pure cis-enantiomers and their mixtures in any mixing ratio and including the racemates.
The enantiomers can be separated in a manner known per se (for example by preparation and separation of appropriate diastereoisomeric compounds). Preferably, a separation of enantiomers takes place at the stage of the starting compounds of the formula III 
for example via salt formation of the racemic compounds of the formula III with optically active carboxylic acids. Alternatively, enantiomerically pure starting compounds of the formula III can also be prepared via asymmetric syntheses.
The tetrazol-5-yl radical R7 of the compounds of the formula I can be bonded to the phenyl radical R6 either in the ortho, meta or para position to the phenanthridine ring.
Those compounds of the formula I are preferred in which the tetrazol-5-yl radical R7 is bonded to the phenyl radical R6 in the meta or para position to the phenanthridine ring. The compounds of the formula I in which the tetrazol-5-yl radical R7 is bonded in the para position are particular preferred in this connection.
Compounds of the formula I in which R1, R2, R3, R31, R4, R5, R51, R6 and R7 have the meanings indicated above and R8 is hydrogen occur in 2 tautomeric forms, which are in equilibrium with one another (1H and 2H form of the tetrazol-5-yl radical). The invention therefore includes both tautomeric forms in any mixing ratio.
By bonding of the substituent R8 (R8xe2x89xa0H) to the tetrazol-5-yl group, the conversion of the two tautomeric forms into one another is blocked. The invention therefore also relates to the 1H- and 2H-tetrazol-5-yl compounds of the formula I substituted by a radical R8 (R8xe2x89xa0H), both in pure form and in any mixing ratio. In this connection, the compounds of the formula I are preferred in which the tetrazol-5-yl radical is substituted in the 2 position by one of the radicals R8 (R8xe2x89xa0H).
The invention further relates to a process for the preparation of the compounds of the formula I, in which R1, R2, R3, R31, R4, R5, R51, A and R6 have the meanings indicated above, and their salts.
a) for the preparation of compounds of the formula I in which R1, R2, R3, R31, R4, R5, R51, R6 and R7 have the meanings indicated above and R8 is hydrogen, reacting corresponding compounds of the formula I, in which R6 is cyanophenyl, with alkali metal azides and halogen salts of ammonia, or
b) for the preparation of compounds of the formula I in which R1, R2, R3, R31, R4, R5, R51, R6, R7 and R8 (R8xe2x89xa0H) have the meanings indicated above, cyclocondensing corresponding compounds of the formula II 
and,
if desired, then converting the compounds of the formula I obtained according to a) or b) into their salts, or, if desired, then converting salts of the compounds of the formula I obtained according to a) or b) into the free compounds.
If desired, compounds of the formula I obtained can be converted into further compounds of the formula I by derivatization. For example, compounds of the formula I in which R6 is a phenyl radical substituted by R7 and R7 is an unsubstituted 1H- or 2H-tetrazol-5-yl radical can be converted into the corresponding substituted tetrazole compounds of the formula I by alkylation reactions, the hydrogen on the tetrazole ring being replaced by the radicals mentioned for R8xe2x80x94excluding hydrogen. The reactions are expediently carried out analogously to the methods known to the person skilled in the art, e.g. by reaction of the 1H- or 2H-tetrazole compounds of the formula I with compounds of the formula R8-X in the presence of a base, R8 having the abovementioned meaningsxe2x80x94excluding hydrogenxe2x80x94and X being a suitable leaving group such as, for example, a chlorine, bromine or iodine atom or an alkylsulfate radical. The 1- and 2-substituted tetrazole regioisomer mixtures usually formed in the alkylation are separated by methods known to the person skilled in the art, such as crystallization or chromatography on suitable support materials. An analogous alkylation of tetrazoles and separation of the regioisomers is described, for example, in J. Med. Chem. 1996, 39, 2354.
The reaction of cyanophenyl derivatives with alkali metal azides and halogen salts of ammonia to give 2-, 3- or 4-(1H- or 2H-tetrazol-5-yl)phenyl derivatives which are unsubstituted in the tetrazole moiety is described, for example, in J. Med. Chem. 1993, 36, 3246.
Cyclocondensation is carried out in a manner known per se to the person skilled in the art according to Bischler-Napieralski (e.g. as described in J. Chem. Soc., 1956, 4280-4282) in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, thionyl chloride or preferably phosphorus oxychloride, in a suitable inert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without further solvent using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling temperature of the solvent or condensing agent used.
Compounds of the formula II, in which R1, R2, R3, R31, R4, R5, R51 and R6 have the meanings indicated above, are accessible from the corresponding compounds of the formula III, in which R1, R2, R3, R31, R4, R5 and R51 have the meanings indicated above, by reaction with compounds of the formula R6-COxe2x80x94X, in which R6 has the meaning indicated above and X is a suitable leaving group, preferably a chlorine atom. For example, benzoylation is carried out as in the following examples according to the Einhorn process, the Schotten-Baumann variant or as described in J. Chem. Soc. (C), 1971, 1805-1808.
Compounds of the formula R6-COxe2x80x94X and compounds of the formula III are either known or can be prepared in a known manner.
Compounds of the formula R6-COxe2x80x94X can be prepared, for example, from the corresponding carboxylic acids R6-COOH, in which R6 has the meaning indicated above, by reaction in a manner familiar to the person skilled in the art.
The compounds R6-COOH, in which R6 has the meaning indicated above, are either known or can be obtained from alkyl 2-, 3- or 4-cyanobenzoates in a manner known to the person skilled in the art, e.g. by reaction with alkali metal azides and halogen salts of ammonia to give alkyl 2-, 3- or 4-(1H- or 2H-tetrazol-5-yl)benzoates which are unsubstituted in the tetrazole moiety. Such a reaction is described, for example, in J. Med. Chem. 1993, 36, 3246. If desired, these intermediates can be converted by alkylation with compounds of the formula R8-X in the presence of a basexe2x80x94as described above for the 1H- or 2H-tetrazole compounds of the formula I or in the abovementioned literaturexe2x80x94into alkyl R6-carboxylates, in which R6 is a phenyl radical substituted by R7, R7 is a 1H- or 2H-tetrazol-5-yl radical substituted by a radical R8 and R8 is not hydrogen, but has one of the other abovementioned meanings for R8. By means of alkaline or acidic hydrolysis conditions familiar to the person skilled in the art, the alkyl R6-carboxylates are converted into the free carboxylic acids R6-COOH.
The compounds of the formula III can be prepared, for example, from compounds of the formula IV 
in which R1, R2, R3, R31, R4, R5 and R51 have the meanings mentioned above, by reduction of the nitro group.
Reduction is carried out in a manner known to the person skilled in the art, for example as described in J. Org. Chem. 1962, 27, 4426 or as described in the following examples. Preferably, reduction is carried out by catalytic hydrogenation, e.g. in the presence of Raney nickel, in a lower alcohol such as methanol or ethanol at room temperature and under normal or elevated pressure. If desired, a catalytic amount of an acid, such as, for example, hydrochloric acid, can be added to the solvent.
The compounds of the formula III, in which R1, R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 together are an additional bond, can be prepared from the corresponding compounds of the formula IV by selective reduction of the nitro group in a manner known to the person skilled in the art, for example in the presence of Raney nickel in a lower alcohol as a solvent using hydrazine hydrate as a hydrogen donor.
The compounds of the formula IV, in which R1, R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 are hydrogen, are either known or can be prepared from corresponding compounds of the formula IV, in which R5 and R51 together are an additional bond. The reaction can be carried out in a manner known to the person skilled in the art, preferably by hydrogenation in the presence of a catalyst, such as, for example, palladium on activated carbon, e.g. as described in J. Chem. Soc. (C), 1971, 1805-1808.
The compounds of the formula IV, in which R5 and R51 together are an additional bond, are either known or can be obtained by reaction of compounds of the formula V 
in which R1 and R2 have the abovementioned meanings, with compounds of the formula VI
R3-CHxe2x95x90C(R4)xe2x80x94C(R4)xe2x95x90CHxe2x80x94R31(VI)
in which R3, R31 and R4 have the abovementioned meanings. Cycloaddition is carried out here in a manner known to the person skilled in the art according to Diels-Alder, e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or in J. Org. Chem. 1952, 17, 581 or as described in the following examples.
Compounds of the formula IV obtained in the cycloaddition, in which the phenyl ring and the nitro group are trans to one another, can be converted into the corresponding cis compounds in a manner known to the person skilled in the art, e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or as described in the following examples.
The compounds of the formula V and VI are either known or can be prepared in a known manner. The compounds of the formula V can be prepared, for example, from corresponding compounds of the formula VII in a manner known to the person skilled in the art, as described, for example, in J. Chem. Soc. 1951, 2524 or in J. Org. Chem. 1944, 9, 170 or as in the following examples.
The compounds of the formula VII 
in which R1 and R2 have the meanings indicated above, are either known or can be prepared in a manner known to the person skilled in the art, as described, for example, in Ber. Dtsch. Chem. Ges. 1925, 58, 203.
The isolation and purification of the substances according to the invention are carried out in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example column chromatography on suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol), which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitation, precipitation with a nonsolvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this manner, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.